This proposal is a request for a Mentored Research Scientist Development Award (K01) for senior fellow researcher Dr. Vladimir Yarov-Yarovoy. The candidate holds advanced degrees in Physics (M.S.) and Biochemistry and Molecular Biology (Ph.D.) and is well trained in the field of Neuroscience. The candidate's ultimate goal is to lead an independent research group, which will conduct fundamental research in the field of neuroinformatics - the interdisciplinary field that bridges research in neuroscience with that in informatics. Successful completion of this proposal will further enhance the candidate's expertise in the field of neuroscience and also will allow him to develop the essential theoretical knowledge and experience in the field of informatics. The candidate's long-term research interests include structure function studies of neuronal ion channels and computational modeling of protein structure, protein-protein, and protein-drug interactions. Dr. Yarov-Yarovoy's training will consist of computational biology and computer programming courses and research work under the dual mentorship of Drs. William Catterall and David Baker. Dr. Catterall is an accomplished investigator in studying the structure and function of the brain voltage-gated sodium and calcium channels. Dr. Baker is an accomplished investigator in predicting the three-dimensional protein structure using novel computational methods. The goal of the project is to develop three-dimensional models of the brain voltage-gated sodium and calcium channels. These models will provide key structural information on the molecular basis of the brain sodium and calcium channel gating, their modulation by second messenger-activated protein phosphorylation and by peptide neurotoxins, and their interaction with therapeutically useful pore-blocking drugs. The novel features of the models will be experimentally tested using site-directed mutagenesis and electrophysiological techniques. The novel computational tools developed in this project will be generalized for structure prediction of other ion channels. Finally, understanding the brain sodium and calcium channel function and modulation on the structural level will lead to a better understanding of mechanisms of neuromodulation, which in turn will give us profound insights into the fundamental mechanisms underlying learning, memory, emotion and behavior.